Dissection of neuropsychiatric-relevant behavioral and structural phenotypes utilizing neuron type-specific ablation of the Bassoon gene in mice

Abstract

Rare pathogenic mutations in the human BSN gene, which encodes the presynaptic cytomatrix protein Bassoon-a key organizer of the neurotransmitter release apparatus have been linked to neuropsychiatric conditions including schizophrenia. Here we began to dissect the potential contribution of Bsn deficiency in distinct populations of mouse (fore)brain neurons on behavioral and anatomical alterations resembling schizophrenia-like phenotypes. To this end, conditional knockout mice lacking Bassoon in subsets of inhibitory synapses (BsnDlx5/6cKO), in forebrain excitatory synapses (BsnEmx1cKO), or at dopaminergic release sites (BsnDATcKO) were generated. The mice were assessed using prepulse inhibition, a paradigm that models sensorimotor gating, which is often impaired in schizophrenia, and a fear/safety learning paradigm. Further, anxiety-related behaviors were evaluated and magnetic resonance imaging (MRI) was performed to assess anatomical brain alterations. Our data reveal synapse-specific effects of the Bassoon deficiency. Sensory gating deficits were observed in both BsnDlx5/6cKO and BsnEmx1cKO mice. BsnDlx5/6cKO mice further demonstrated impaired discrimination between conditioned fear and safety-a condition frequently observed in individuals with schizophrenia. By contrast, BsnDATcKO mice displayed enhanced discrimination between conditioned fear and safety. All mouse strains showed elevated anxiety-like behavior in the light/dark box. Structural MRI revealed increased brain volumes in BsnDlx5/6cKO and BsnEmx1cKO mice, with the most pronounced changes in the hippocampus and cortex. Previous studies have shown that BsnDlx5/6cKO mice display autistic-like behaviors, altered hippocampal network activity and epilepsy. Our findings support the notion that deficits in Bsn-mediated functions, particularly in interneurons, may contribute to the etiology of neurodevelopmental and neuropsychiatric conditions.